Antibiotic-associated diarrheal diseases are caused by enterotoxin producing strains of Clostridium difficile, Staphylococcus aureus and Clostridium perfringens, and represent a major economic burden to the healthcare system, that is conservatively estimated at $3-6 billion per year in excess hospital costs in the U.S. alone.
Clostridium difficile associated diarrhea (CDAD) is the most common cause of infectious, hospital-acquired diarrhea in the United States, and its incidence is increasing. With some estimates of its incidence as high as 3 million cases/year, it is clearly a major nosocomial infectious disease. The illness is caused by Clostridium (C.) difficile, an anaerobic, spore forming, Gram-positive bacterium that produces two enterotoxins (A and B). The spectrum of CDAD may range from mild, self-limited diarrhea to fulminant, life-threatening pseudomembranous colitis.
The two most important risk factors for CDAD are recent exposure to an antibiotic and exposure to a toxin-producing strain of the organism. Patients treated with clindamycin appear to be highly susceptible to CDAD presumably due to its prolonged effects on the indigenous anaerobic bowel flora. Host susceptibility also appears to be a critical factor in the development of CDAD since asymptomatic colonization is the most common outcome after exposure to the organism. Indeed, a recent report suggests that increased serum levels of immunoglobulin G against toxin A are associated with asymptomatic carriage of the organism post-exposure.
There are currently two dominant therapies for CDAD: vancomycin and metronidazole. While only vancomycin is approved by the Food and Drug Administration (FDA) for this indication, metronidazole is recommended as initial therapy out of concern for the promotion and selection of vancomycin resistant gut flora, especially enterococci. Oral bacitracin has also been used for the treatment of CDAD, although very infrequently. Recently there have been reports of C. difficile tolerance or resistance to vancomycin and metronidazole (Pelaez et al., Antimicrob. Agents Chemother. 46:1617-1618, 2002; Pelaez et al., Antimicrob. Agents Chemother. 46:1647-1650, 2002). While both vancomycin and metronidazole are generally very well tolerated and effective, allergies, intolerances, and side effects to both agents do occur.
Broad spectrum, anti-anaerobic agents such as metronidazole have also been shown to increase the density of vancomycin-resistant enterococcus (VRE) in the stool of colonized patients, and patients with CDAD may be at greater risk for VRE bacteremia in some populations. Given the limited therapeutic alternatives for the treatment of CDAD, and incipient reports of resistance, new therapies are needed.